tbuckley/cabot-search huggingface dataset:
Abstract 5602: Markers of hypoxic cells: Testing a pre-clinical detection assay
Authors: Beatriz Zayas, Karoline Rios, Luis Ortiz, Osvaldo Cox
Journal: Cancer Research (2023)

Abstract The proposed project aims to test the applicability of a novel set of patented organic compounds as markers of hypoxic circulating tumor cells (H-CTC) with potential pre-clinical relevance. Circulating tumor cells (CTC) are individual cells or clusters that can move from tumors to circulation invading other tissues. Often cells in the tumor need to adapt to low oxygen levels, generating a population of cells known as hypoxic cells that can survive low oxygen levels. These hypoxic cells can produce more cell junction proteins, augmenting connections between cells causing them to break away in clusters rather than individually. Clustered CTCs are much more efficient at metastasis formation. Release of CTC can also be stimulated by cancer treatments such as radiation and chemotherapy. To date, our research has generated in-vitro studies with a set of 3-nitrobenzazolo[3,2- a]quinolinium chloride salts (NBQS) demonstrating its capacity as markers of hypoxic human cancer cells in vitro. Comparison with the control Pimonidazole demonstrated the advantages of novel NBQ-TOM compounds as hypoxic marker. We here, aim to test the applicability of NBQS to identify hypoxic cells among circulating tumor cells (H-CTC). To date limited commercially CTC detection methods are available. Our application can be described as pre-clinical detection technology of hypoxic cancer cells serving also in cancer management. To determine the capacity of novel compound, NBQ-345 TOM as hypoxic fluorescent marker, colon tumor cells (COLO 205) are culture under hypoxic and aerobic environment and treated with NBQ-345TOM (25uM) for 24 hours. After treatment fluorescence is measured with an OPTIMA BMG Fluorimeter. Fluorescence emission results demonstrated significant formation of the NBQ-234 TOM fluorescent metabolite on hypoxic tumor cells in contrast to cells treated under aerobic environment. Also, fluorescence microscopy analysis of colon cancer cells treated for 24 hours with NBQ-345 TOM at hypoxic and aerobic conditions confirmed the stronger fluorescence generation at hypoxic conditions in contrast to cells at aerobic conditions. Citation Format: Beatriz Zayas, Karoline Rios, Luis Ortiz, Osvaldo Cox. Markers of hypoxic cells: Testing a pre-clinical detection assay. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5602.
Abstract 6459: Developed and persistent dyslipidemia is associated with increased risk of gastric cancer in a prospective study
Authors: Dan Huang, Woo-Kyoung Shin, Katherine De la Torre, Sukhong Min, Aesun Shin, Jong-Koo Lee, Hyung-Ho Kim, Daehee Kang
Journal: Cancer Research (2023)

Abstract Background: Increasing evidence suggests that metabolic disorders are a risk factor for gastric cancer. However, there is a lack of evidence on whether changes and persistence of metabolic disorders affect the subsequent gastric cancer occurrence. Therefore, this study aimed to evaluate the effects of changes or persistence in metabolic syndrome and its components' status on the incidence of gastric cancer among Korean population. Methods: This study comprised 59,671 individuals from the Health Examinees Study who had baseline surveys from 2004 to 2012 and repeated measurements from 2012 to 2016; and were followed up until 2018. Metabolic syndrome and its components were defined according to the National Cholesterol Education Program Adult Treatment Panel III and modified based on Korean population criteria. Participants were categorized into free, developed, recovered, and persistent metabolic syndrome and its components. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for gastric cancer incidence using multivariable cox proportional hazard models with age as a time scale. Results: During the mean follow-up of 9.4 years, 312 subjects were newly diagnosed with gastric cancer. Compared with the metabolic syndrome-free group, the persistent group had a higher incidence of gastric cancer (HR 1.37, 95% CI 1.02-1.84). Among individual components, the developed-high triglycerides group had the highest gastric cancer incidence (HR 1.52, 95% CI 1.12-2.05), followed by the persistent group (HR 1.40, 95% CI 1.04-1.90) compared to the free group. The low HDL-cholesterol persistent group (HR 1.45, 95% CI 1.08-1.93) showed a higher incidence than in the free group. In the subgroup analysis, we found association between high triglycerides developed and gastric cancer in men, while for women, the associations were significant between high triglycerides and low HDL-cholesterol persistent groups and gastric cancer incidence. Conclusions: In this prospective cohort study, we found that developed or persistent dyslipidemia, assessed as abnormal triglycerides and low HDL-cholesterol, were associated with an increased incidence of gastric cancer. These findings suggest that effective management of dyslipidemia may reduce gastric cancer risk. Keywords: Gastric cancer, Dyslipidemia, Metabolic syndrome, Prospective cohort Citation Format: Dan Huang, Woo-Kyoung Shin, Katherine De la Torre, Sukhong Min, Aesun Shin, Jong-Koo Lee, Hyung-Ho Kim, Daehee Kang. Developed and persistent dyslipidemia is associated with increased risk of gastric cancer in a prospective study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6459.
Abstract 3616: Investigating proto-oncogene PBF-induced cell migration and invasion
Authors: Merve Kocbiyik, Selvambigai Manivannan, Ling Zha, Katie Brookes, Martin L Read, Chris J McCabe, Vicki E Smith
Journal: Cancer Research (2023)

Abstract The proto-oncogene pituitary tumor transforming gene binding factor (PTTG1IP/PBF) is overexpressed in multiple tumors and associated with tumor progression. PBF mediates several tumorigenic processes, including cell motility, whereby it potently induces cancer cell migration and invasion. PBF is phosphorylated by Src kinase at Y174 and mutation of this residue (Y174A) renders PBF unable to induce cell invasion, suggesting that phosphorylation mediates the stimulation of cancer cell motility by PBF. This study aimed to further elucidate the mechanism of PBF-induced cell motility. PBF-Y174 is also the key residue in a YXXΦ endocytosis motif. Both PBF phosphorylation and endocytosis were found to be essential for PBF-induced cell motility as mutants which disrupted either process were unable to stimulate thyroid and breast cancer cell migration and invasion. To elucidate molecular events downstream of PBF overexpression, phosphoproteomic and RNA-Seq analyses of normal thyroid cells (Nthy-ori 3-1) with stable PBF overexpression were performed and showed an enrichment in molecules involved in cell adhesion and cytoskeleton organisation. These findings prompted further investigation into a physiological role for PBF in cell motility. We utilised a novel Pbf knockout (Pbf−/−) mouse model generated through CRISPR/Cas9-mediated deletion of Pbf exon 4 in C57BL/6N mice to determine the impact of Pbf deletion on cellular mechanisms. Mouse embryonic fibroblasts (MEFs) were isolated at embryonic day 13.5 and used as primary cultures. Pbf−/- MEFs showed a significant reduction in migration and invasion compared with wild-type (Pbf+/+) MEFs. Interestingly, the loss of one functional copy of Pbf in heterozygote MEFs (Pbf+/−) resulted in an intermediate decrease in motility suggesting a gene-dosage effect. Initial immunofluorescent studies of Pbf−/− MEFs suggest alterations in focal adhesions (FAs). In Pbf+/+ MEFs focal adhesion kinase (FAK) and paxillin staining highlighted FA structures that were normally elongated and aligned with actin stress fibers. In contrast, Pbf−/- MEFs demonstrated a significant reduction in FAK and paxillin staining with smaller, punctate and more radially distributed FAs. These studies demonstrate a physiological role for PBF in cell adhesion and migration and further elucidate the mechanism by which PBF induces cell motility in tumor progression. Citation Format: Merve Kocbiyik, Selvambigai Manivannan, Ling Zha, Katie Brookes, Martin L Read, Chris J McCabe, Vicki E Smith. Investigating proto-oncogene PBF-induced cell migration and invasion. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3616.
Abstract 6244: Design, synthesis, and structure-activity relationships of substituted pyrido[3,2-<i>d</i>]pyrimidines as microtubule targeting agents and anti-cancer agents
Authors: Yesha Vijaykumar Shah, Ruoli Bai, Ernest Hamel, Aleem Gangjee
Journal: Cancer Research (2023)

Abstract Microtubules (MTs) are composed of αβ-tubulin heterodimers and are essential components of the cellular cytoskeleton involved in critical cellular functions, including mitosis, cell migration and signaling, intracellular trafficking, and angiogenesis. Microtubule targeting agents (MTAs) are highly successful chemotherapeutic agents because they target MT dynamics and interfere with MT-dependent cellular processes. The clinical efficacy of MTAs is limited by multidrug resistance due to expression of the P-glycoprotein (Pgp) drug efflux pump or increased expression of βIII-tubulin. This necessitates the development of novel MTAs effective against cell lines expressing these forms of drug resistance, which could offer potential advantages in patients who fail to respond to current MTAs, such as paclitaxel. Previously, we reported colchicine site (CS) binding compound 1 with a pyrido[3,2-d]pyrimidine scaffold and a 2-H substitution and N4-4’-methoxyaniline substitution inhibited colchicine binding and tubulin assembly (87% inhibition at 5 µM and IC50 = 1.3 µM, respectively). Compounds 2-9 were designed with a 2-CH3 substitution to evaluate the structure-activity relationships at the 4-position by using conformational restriction and isosteric replacements. Compounds 2-9 were synthesized, and the biological evaluation showed that compounds 2-9 inhibited tubulin assembly (7, IC50 = 0.72 μM) and binding of colchicine to tubulin (7, 97% inhibition at 5 µM, 81% at 0.5 µM). Compound 7 was found to be highly potent in the MCF-7 breast cancer cell line with an IC50 of 2.5 nM which was ~3.5-fold better than combretastatin-A4 (CA4). Compound 7 inhibited the growth of the human ovarian cancer cell line OVCAR-8 with an IC50 = 3.0 nM. For the Pgp overexpressing cell line NCI/ADR-RES, 7 was equally potent (IC50 = 3.0 nM), whereas paclitaxel was almost inactive (IC50 = 1,500 nM). Thus, we have identified 2-CH3 substituted pyrido[3,2-d]pyrimidines as a novel structural scaffold for inhibition of tubulin assembly and colchicine binding that have potent cytotoxic activity against the breast cancer cell line MCF-7 and against both the parental ovarian cancer cell line OVCAR-8 and its derivative Pgp overexpressing cell line NCI/ADR-RES. These compounds thus merit further study as potential cancer chemotherapeutic agents. Citation Format: Yesha Vijaykumar Shah, Ruoli Bai, Ernest Hamel, Aleem Gangjee. Design, synthesis, and structure-activity relationships of substituted pyrido[3,2-d]pyrimidines as microtubule targeting agents and anti-cancer agents. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6244.
Abstract 1333: A novel and highly efficient biomimetic capture approach for the isolation and characterization of circulating metastatic cancer cell clusters from lung cancer patients
Authors: Kourosh Kouhmareh, Erika Martin, Darren Finlay, Anukriti Bhadada, Francisco Downey, Jeff A. Allen, Peter Teriete
Journal: Cancer Research (2023)

Abstract Capture and isolation of circulating metastatic cancer cell clusters (MCCC) is the essential first step to identify novel therapeutic targets focused on this important route of metastasis. We developed a unique biomimetic capture approach that allows selective isolation of these deadly clusters from the whole blood of lung cancer patients. Utilizing a microfluidic platform we developed a versatile smart-coating that combines biomimicry and immuno-capture for a highly efficient and selective isolation of viable MCCCs. Here we show the capture and characterization of multiple MCCCs from non-small cell lung cancer (NSCLC) patients. Table 1 shows the count of clusters detected in NSCLC patients based on a stringent criterion confirming their identification. The MCCCs were detected in every patient tested but none were detected in normal blood controls from donors of similar age. Isolated MCCC where characterized by immunofluorescence and submitted for genomic analyses. Metastasis remains one of the leading causes of cancer related deaths worldwide. Insights into how the tumor propagates to pre-metastatic sites is necessary to develop focused therapeutic approaches. Circulating metastatic cancer cell clusters (MCCCs) have been established as a primary entity causing distal metastases. Significant advances have been made linking cluster integrity and viability to increased metastatic potential highlighting the unmet need for cluster focused therapies. Our novel approach allows the rapid and easy capture of MCCCs paving the way for the discovery of novel or unique targets that eventually will bring new anti-metastatic therapies to the clinic. Table 1 Patient Age/Sex Staging/Metastasis #MCCC INMC-044.1 82 M IVB/bone 2 INMC-044.2 53 F IV/bone 1 INMC-044.3 59 F IV/bone, brain 2 INMC-044.4 65 M IV/thoracic cav., lung 1 INMC-044.5 67 M IIIa/none 3 Normal Blood 54 F N/A 0 Normal Blood 68 M N/A 0 Citation Format: Kourosh Kouhmareh, Erika Martin, Darren Finlay, Anukriti Bhadada, Francisco Downey, Jeff A. Allen, Peter Teriete. A novel and highly efficient biomimetic capture approach for the isolation and characterization of circulating metastatic cancer cell clusters from lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1333.
Abstract 4408: Provisional prognostic score for monomorphic epitheliotropic T-Cell lymphoma
Authors: Philip A. Haddad, Dinesh Keerty, Neelakanta Dadi
Journal: Cancer Research (2023)

Abstract Background: Monomorphic Epitheliotropic Intestinal T-cell Lymphoma (MEITL) is a rare extranodal intestinal PTCL. It is an aggressive disease with an overall poor prognosis. However, the disease presents a diverse spectrum of survival outcomes. We conducted this study to develop a provisional MEITL prognostic score (MPS) for this rare disease. Methods: We used our updated MEITL database, which contains retrospective data on 218 cases. Such data included demographics such as sex, age, and race. It also included disease presentation symptoms, duration of symptoms before diagnosis, site(s) of the disease, stage, blood counts, disease immune and molecular phenotype, types of treatment, quality of response, and survival outcomes. Out of the 218 cases, only 140 cases had complete survival and outcomes data, the sample chosen for this study. Cox proportional-hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on overall survival (OS). Due to the relatively small training cohort, we included factors that statistically impacted OS as well as factors that numerically trended that way. Results: The median OS of the cohort was 11 months. The following dichotomous variables were identified as impactful prognostic factors in this cohort: Bone marrow involvement (9 vs. 14 months), Non-biclonal TCR status (10 vs. 17.5 months), CD56+ (10 vs. 26 months), Ki67&amp;gt;70% (4 vs. 8 months), cMyc expression &amp;gt;15% (7 vs. 12 months). A prognostic model was devised using these variables to identify different levels of risk. Each variable was assigned a score of 1 when present, except for cMyc, which was assigned 2 points for having the highest hazard ratio among all the variables. In this exploratory cohort, low risk was assigned a score of 0, intermediate risk a score of 1-2, and high risk a score of 3-6. This prognostic score system led to our cohort's most optimal risk discriminatory model, where low, intermediate, and high risk had a median OS of 26, 12, and 4 months, respectively (p=0.002). Conclusion: This MPS is a promising new tool for risk-stratifying patients with MEITL. However, it still needs prospective validation. Citation Format: Philip A. Haddad, Dinesh Keerty, Neelakanta Dadi. Provisional prognostic score for monomorphic epitheliotropic T-Cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4408.
Abstract 6240: The potent quadruplex-binding compound QN-302 shows anti-tumor activity as a monotherapy in an orthotopic <i>in vivo</i> model of pancreatic cancer
Authors: Nicole Williams, Danielle Santos, Jenny Worthington, Ahmed Ahmed, Tariq Arshad, Stephen Neidle
Journal: Cancer Research (2023)

Abstract The compound QN-302, a tetra-substituted naphthalene diimide derivative has single-digit nM anti-proliferative activity in a panel of human pancreatic cancer (PDAC) cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644). It has significant anti-tumor activity in the MIA-PACA2 xenograft model for PDAC and in the genetic KPC model. We now report that this compound also shows significant mono-therapy anti-tumor activity in an orthotopic model for PDAC. Female athymic nude mice bearing orthotopically implanted pancreatic BxPC-3 cells were dosed with 1 x weekly IV QN-302 at 0.5 and 1.0 mg/kg, over a period of 21 days. A separate group of mice was treated with Gemcitabine twice weekly IV during this period, at a dosage of 15 mg/kg. Blood samples from animals were collected on a weekly basis and were used to detect and quantify circulating tumor DNA as a method of following treatment efficacy. In line with previous studies QN-302 was well-tolerated at 0.5 and 1.0 mg/kg with no adverse effects on animal health or behavior noted during the study. Circulating tumor DNA levels were significantly less than vehicle controls in gemcitabine-treated animals from day 7 and QN-302 (1.0 mg/kg) treated animals from day 14 of treatment. Survival was significantly increased in gemcitabine and QN-302 (1.0 mg/kg) QW treatment groups. Statistically significant efficacy was observed in gemcitabine and QN-302 (1.0 mg/kg) treated animals. Examination of blood chemistry and biochemistry of treated animals did not indicate any adverse effects due to QN-302. This orthotopic model is the 4th in vivo study in a pancreatic cancer model showing anti-tumor activity for QN-302, further confirming the potential of this compound for human disease. QN-302 is currently in an advanced stage of pre-IND development by Qualigen Inc. Citation Format: Nicole Williams, Danielle Santos, Jenny Worthington, Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The potent quadruplex-binding compound QN-302 shows anti-tumor activity as a monotherapy in an orthotopic in vivo model of pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6240.
Abstract 6431: Targeting Rab7-mediated STING degradation to amplify therapeutic STING agonism in TNBC
Authors: Yuqing Zhang, Jessica L. Ritter, Tran C. Thai, Deborah A. Dillon, David A. Barbie, Thanh U. Barbie
Journal: Cancer Research (2023)

Abstract STING (Stimulator of interferon genes), encoded by TMEM173, is a critical regulator of the innate immune response to cytoplasmic double stranded DNA in cancer and is actively being pursued as a target for cancer immunotherapy. STING agonist analogues of 2’-3’cGAMP, the cyclic dinucleotide that directly activates STING downstream of cyclic-GAMP synthase, have entered phase 1 clinical trials for triple negative breast cancers (TNBC). Recently, we have identified tumor cell Phosphatase and tensin homolog (PTEN) inactivation as a precision-based context in which to apply STING agonists. Mechanistically, PTEN null TNBCs maintain Ras-related protein Rab-7a (Rab7) in an inactive state and therefore trafficking of STING to the lysosome is impaired and cells are rendered hypersensitive to STING agonism. Tissue microarray analysis reveals high STING expression in PTEN null TNBCs. Consistently, PTEN null TNBC cell lines were hyper-responsive to STING agonists with increased downstream production of IRF3 targets including CXCL10. In contrast, PTEN wild-type cells exhibit low STING expression and modest sensitivity to STING agonism. As such, although a significant proportion of TNBCs are PTEN null, we sought to broaden these findings to PTEN wild-type TNBCs by genetically and pharmacologically mimicking the PTEN null state by Rab7 knockout and use of a novel selective Rab7 inhibitor, CID1067700. Indeed, using the PTEN wild-type TNBC cell line, MDA-MB-231, we found that PTEN deletion robustly increased STING protein expression. Rab7 CRISPR-Cas9 knockout or treatment of MDA-MB-231 cells with CID1067700 and the STING agonist (ADU-S100) impaired trafficking of STING for lysosomal degradation, upregulated T cell chemokines, and enhanced growth inhibition. Next, to model the potential in vivo implications for immune cell recruitment and function, we used a 3D microfluidic T-cell migration assay. We found that the enhanced CXCL10 levels resulting from addition of CID1067700 to MDA-MB-231 cells led to T-cell recruitment to the tumor spheroids. Taken together, our study identifies PTEN null status as a specific genomic context in TNBC that has exquisite sensitivity to STING agonist therapy and combination with Rab7 inhibition could amplify therapeutic STING agonism in PTEN wild-type TNBCs. Citation Format: Yuqing Zhang, Jessica L. Ritter, Tran C. Thai, Deborah A. Dillon, David A. Barbie, Thanh U. Barbie. Targeting Rab7-mediated STING degradation to amplify therapeutic STING agonism in TNBC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6431.